1

Received date: 10/15/2010

Accepted date: 04/05/2011

Australian Guidelines for the assessment of iron overload and iron

chelation in transfusion-dependent thalassaemia major, sickle cell

disease and other congenital anaemias. *

Short Title: Iron chelation in the haemoglobinopathies

Ho PJ,1* Tay L,2 Lindeman R,3 Catley L,4 Bowden DK.5

*Corresonding Author

1. Senior Staff Haematologist and Clinical Associate Professor, Institute of

Haematology, Royal Prince Alfred Hospital, Missenden Road,

Camperdown, NSW 2050; Bosch Institute, University of Sydney.

Tel (02) 95158457

Fax (02) 95156698

2. Dept. of Haematology, Royal Adelaide Hospital, North Terrace, Adelaide,

SA 5000

3. Department of Haematology, Prince of Wales Hospital, Barker Street,

Randwick NSW 2031

This is an Accepted Article that has been peer-reviewed and approved for publication in the Internal Medicine Journal, but has yet to undergo copy-editing and proof correction. Please cite this article as an “Accepted Article”; doi: 10.1111/j.1445-5994.2011.02527.x

2

4. Dept. of Haematology, Mater Hospital, Raymond Terrace, South Brisbane,

QLD 4101

5. Thalassaemia Services Victoria, Monash Medical Centre, 246 Clayton Rd,

Clayton, VIC 3168

Word Count (Abstract): 146

Word Count (Main text): 4413

ABSTRACT

Iron overload is the most important cause of mortality in patients with

thalassaemia major. Iron chelation is therefore a critical issue in the

management of these patients and others with transfusion-dependent

haemoglobinopathies and congenital anaemias. In recent years, significant

developments have been made in the assessment of iron overload, including

the use of MRI for measuring liver and cardiac iron. Advances in the modalities

available for iron chelation, with the advent of oral iron chelators including

deferiprone and deferasirox in addition to parenteral desferrioxamine, have

expanded treatment options. A group of Australian haematologists have

convened to formulate guidelines for managing iron overload on the basis of

available evidence, and to describe best consensus practice as undertaken in

major Australian Haemoglobinopathy units. The results of their discussions are

3

described in this article, with the aim of providing guidance in the management

of iron overload in these patients.

Key Words: Thalassaemia, Haemoglobinopathy, Iron overload, Iron chelation

INTRODUCTION

The transfusion-dependent haemoglobinopathies and congenital anaemias are

a significant problem in a country such as Australia with a population of diverse

ethnic origins, where increasing numbers of patients with haemoglobinopathies

such as thalassaemia and sickle cell disease are treated. While patients with

beta-thalassaemia major are transfusion-dependent, a proportion of sickle cell

disease patients also undergo regular transfusion to prevent severe

complications such as recurrent, severe sickling crises. Iron overload is one of

the most critical issues in these patients, and complications of iron overload

remain the most important cause of mortality 1, 2 Iron chelation is therefore

crucial in the management of these patients to prevent complications such as

cardiomyopathy, the predominant cause of premature death, liver fibrosis and

cirrhosis, and endocrinopathies including growth failure, abnormal sexual

development and infertility, hypothyroidism and diabetes. An important factor in

suboptimal iron chelation and poor prognosis is the lack of adherence.2, 3

4

For several decades, the only available iron chelator was desferrioxamine, for

which there is the longest cumulative experience and evidence of efficacy.4 Two

oral chelators have come into the clinic in recent years - deferiprone and

deferasirox. At the same time, advances have been made in the assessment of

tissue iron load, especially with the development of MRI assessment of liver and

cardiac iron, enabling the adjustment of therapy according to organ iron load.

It has been increasingly recognised that therapy should be tailored to specific

patient needs, within the context of standard recommendations and consensus

best practice. This has highlighted the benefit of compiling guidelines on iron

chelation in this group of patients. As a result, a group of Australian

haematologists and paediatricians involved in the care of haemoglobinopathy

patients has convened to discuss clinical protocols, to try to define “best

practice” in Australia; and where there are uncertainties due to the lack of

evidence, to define consensus practice according to extensive collective

experience.

A range of guidelines have been published by national, international and

institutional groups.5-10 The Australian panel reviewed these recommendations

as a background to describing our practice and formulating the following

consensus opinion.

5

A. Measurements of iron load and pathophysiological significance

Parameters used to monitor iron load include serum ferritin, liver biopsy, MRI

assessment of liver and cardiac iron, in conjunction with functional testing such

as echocardiography and measures of endocrine function. Dual energy CT for

measurement of liver iron has also been performed in some centres.11 Each of

these parameters has a different role. While serum ferritin is valuable due to its

ease of measurement and wide availability, it has significant limitations as the

levels can reflect confounding factors such as inflammation. In contrast MRI

technology has enabled accurate and specific measurement of organ iron load,

providing a more efficacious means of tailoring therapy to individual risk, but

availability is currently restricted and should be improved.

I. Serum Ferritin

Serum ferritin is the most commonly used parameter for monitoring iron

overload. It correlates with cardiac impairment and survival,4 but can be

elevated by many confounding factors, including acute phase reactions such as

infections, inflammation or malignancy, or by hepatic damage. It has a poor

correlation with hepatic iron.4 Nevertheless, the close relationship between

serum ferritin and survival and its relative ease of measurement makes it the

most practical parameter for sequential monitoring.

In most Australian haemoglobinopathy units, serum ferritin is measured

monthly, providing regular feedback to both the physician and patient. However

6

due to the possible confounding factors above, the values should not be

interpreted in isolation, as the trend over a longer period such as 3 months is

more informative and should form the basis of the assessment. Serum ferritin

has therefore been a very important parameter for monitoring iron chelation,

using the available iron chelators of desferrioxamine, deferiprone and

deferasirox (see Section B). On the basis that very few patients with a serum

ferritin level consistently within the range of 1000-1500 μg/L develop cardiac

iron loading, this has been considered to be a reasonable target, although the

optimal target may still be reduced with future studies. The incidence of side

effects of desferrioxamine and deferasirox may be increased at serum ferritin

levels less than 500 μg/L, and this is the basis for a recommendation not to

reduce the serum ferritin below this level using these chelating agents. There is

no similar recommendation for patients taking deferiprone. Recent studies have

indicated that low ferritin levels and hepatic iron may be associated with a

significant reduction in morbidities without an increase in adverse events.12, 13

II. Liver biopsy

Liver biopsy was previously considered to be the gold standard of liver iron

assessment, but is an invasive procedure associated with risk of complications

and is subject to sampling error. Liver biopsy is still performed to evaluate liver

fibrosis, cirrhosis or hepatocellular carcinoma which are possible complications

in all patients with liver iron overload, particularly in those with coexisting

hepatitis C.

7

III. MRI assessment of liver iron

The quantitation of liver iron by MRI is one of the most significant recent

advances in iron monitoring.14 The most widely adopted method is based on the

measurement of tissue proton transverse relaxation rates (R2), showing

excellent correlation with liver iron concentration (LIC) measured by biopsy.14

Algorithms predicting risk of complications from liver biopsy LICs have been

applied to LICs obtained by MRI (see Table I), and hepatic iron remains the

best measure of total body iron loading.15

Although this procedure is not yet widely available in Australia, the expert panel

considers it to be a very useful method of monitoring liver iron load and in

directing iron chelation therapy. An appropriate monitoring strategy would

comprise annual R2 MRI for the majority, while this can be extended to every 2

years for patients with normal LIC or at the lower end of the ideal range (e.g. 3 –

5 mg/g dry weight) when there has been no change to chelator regimen, and

perhaps increased to every 6 months in at-risk patients, such as those with LIC

above 15 mg/g dry weight. LIC results should also be correlated with standard

liver function tests.

IV. MRI assessment of cardiac iron

The most important cause of premature death in thalassaemia major is iron-

overload cardiomyopathy.1, 2 MRI has been successfully applied to quantify iron

8

content in the heart. The most widely adopted measure is T2*, a relaxation

parameter intrinsic to protons placed under the magnetic field.16 Due to

accessibility and cost, availability of this procedure is still restricted in Australia.

The correlation between cardiac T2*, cardiac iron loading and its utility in

predicting cardiac events has been validated.16, 17 The panel considers cardiac

MRI to be a very important means of monitoring cardiac iron load. Ideally

cardiac MRI should be monitored at least annually. In at-risk patients, such as

those with T2* indicative of severe iron load (<10 ms) or in those patients who

already have impaired cardiac function, cardiac MRI should be performed every

6 months. For stable patients with normal cardiac iron (T2* >20 ms), monitoring

every 2 years is likely to be adequate. The measurements of T2* and their

implications on cardiac risk are summarised in Table II. Cardiac MRI can also

provide measurements of ejection fraction and ventricular mass, but an annual

assessment of cardiac function (ejection fraction) by either echocardiography or

gated heart pool scan remains very important. An abnormal ejection fraction is

indicative of very severe iron load associated with a high risk of mortality, thus

the aim should be to detect increased iron load by MRI before the development

of overt cardiomyopathy.

V. Additional comments on MRI assessment of total body iron

While the measurement of liver and cardiac iron by MRI are important

developments in facilitating the tailoring of iron chelation therapy, it is important

to note that discrepancies between liver and cardiac iron load can be observed.

9

This is likely to be due to differences in kinetics of iron loading and clearance

between the liver and heart, with a time-lag in cardiac iron loading and

clearance.18 Hence while LIC has been used to indicate the risk of

complications of increased total body iron load including the heart (Table I), it is

emphasised that a low level of liver iron can still be associated with abnormal

cardiac iron accumulation. Thus the panel considers it an important goal for

both liver and cardiac MRI assessments to be made available to all patients.

MRI assessment of iron load in endocrine glands, including the pancreas and

pituitary gland, is currently under development.19, 20 These are presently

research methods and have not yet been incorporated into routine clinical

practice.

VI. Labile plasma iron (LPI)/ Non-transferrin bound iron (NTBI)

LPI and NTBI are toxic iron species in the circulation, not bound to transferrin,

which mediate cellular iron damage through an increase in the labile cellular

iron pool.21 The three available iron chelators (desferrioxamine, deferiprone and

deferasirox) have been evaluated with respect to their effect on LPI. Although

desferrioxamine suppresses LPI during the infusion, once it is stopped a

significant rebound in LPI may occur which may lead to increased toxicities.21

Deferiprone administered at the recommended schedule of three times a day

suppresses LPI, but the levels show significant fluctuation and are more

persistently reduced by the addition of desferrioxamine.21 Deferasirox has a

10

longer half-life of approximately 16 hours, and 24-hour suppression of LPI has

been shown to be achieved by once daily treatment.21 At present, LPI and NTBI

are mainly applied in research, but may be useful in determining the risk of

organ toxicity and the effectiveness of iron chelation as the assays become

more widely available.

11

B. Modes of chelation

I. Available chelators

The properties of the three iron chelators approved for clinical use –

desferrioxamine, deferiprone and deferasirox - are summarised in Table III. An

accurate estimation of transfusion iron intake is important in the choice and

dosing of iron chelation.22 Most Australian units transfuse at four-weekly

intervals, aiming for a pre-transfusion haemoglobin level of 90-100 g/L. All three

available iron chelators exhibit dose-dependent iron chelation. As

desferrioxamine has poor oral bioavailaibility and a short half-life (20-30 min), it

is infused subcutaneously or intravenously, whereas deferiprone and

deferasirox are oral agents. Deferiprone has a half-life of 3-4 hours and is

therefore administered three times a day. In contrast, deferasirox has a half-life

of 8-16 hours and can be administered daily. Toxicities are also different as

noted in Table III.

II. When and how to start chelation

Previous guidelines have generally recommended starting chelation after 10-20

units packed red cells transfused and when ferritin exceeds 1000 μg/L or lies

between the range of 1000-2500 μg/L.5-10 Australian practice is largely

consistent with these recommendations. Paediatric haematologists often

commence chelation after 12-18 months of transfusions, when the serum ferritin

usually (but not necessarily) lies between 1500 and 2000 μg/L. Chelation by

12

desferrioxamine is usually not started until the patient is aged 4-5 years, due to

concern regarding the adverse effect of desferrioxamine on bone development

and growth. The treatment dose is 30-60 mg/kg/day infused subcutaneously

over 8-10 hours by infusion pump for 5-7 days per week.

Thus while it is rare to start chelation between 2 and 4 years, deferasirox should

be the preferred option in this age group, as clinical trials of this agent have

included a significant number (up to ~600) of patients between 2 and 6 years,13,

23 with no increase in the incidence of side-effects. The starting dose should be

20-30 mg/kg/day. In Australia, deferasirox can be used from the age of 6 years

as a first line agent, and if other chelation (i.e. desferrioxamine) is ineffective or

contraindicated at 2 – 6 years; as noted above desferrioxamine is

contraindicated before the age of 4 years.

There are limited data on the use of deferiprone in children. In Australia

deferiprone is approved as second line therapy if desferioxamine is ineffective.

One study of 44 patients under the age of 6 years noted a significant increase in

reversible thrombocytopenia (45.5%) occurring 3 months to 1 year after

commencing treatment, but no other increased side-effects specific to this age

group.24 A liquid formulation of deferiprone is available and there is early

experience reporting efficacy in reducing serum ferritin in a paediatric

population, but a 2% incidence of agranulocytosis and 6% risk of neutropenia

were also observed.25

13

Summary of main points – When and how to start chelation

a. Chelation is started after 10-20 transfusions, and when serum ferritin is in

the range of 1000-2500 μg/L; this usually occurs after 12-18 months of

transfusion and after 2 years of age.

b. In general chelation can be delayed until 4 years without any significant

known detrimental effect.

c. Children aged 4-6 years are started on desferrioxamine, and if this is not

effective, can be changed to deferasirox.

d. Children over 6 years can be started on desferrioxamine or deferasirox,

with an increasing trend towards using deferasirox in first line; currently

deferiprone is licensed in Australia in second line.

III. Choice of agent in continuing iron chelation

For many years, desferrioxamine has been the only available iron chelator.

While clearly efficacious,4 parenteral administration can be a significant

impediment to adherence.3 Several studies have found significant numbers of

patients on desferioxamine with abnormal cardiac iron, but this is most likely

due to poor adherence,26 and under-dosing in some cases. Not surprisingly

many patients changed from desferrioxamine to one of the two oral agents

when they became available. However some patients who have been well-

14

chelated on desferrioxamine have chosen to remain on this drug, which remains

an appropriate option if compliance is maintained and there is no excessive iron

load.

The choice between deferiprone and deferasirox has not only been influenced

by clinical data, but also by the “history” of individual units. The development of

deferiprone pre-dated deferasirox. Some units which used deferiprone from

early in its development continued to do so, converting to deferasirox or

desferrioxamine only when patients demonstrated intolerance or failure. Other

units did not use deferiprone due to initial concerns of liver fibrosis (which have

been refuted)27 and other toxicities such as neutropenia and arthritis, and

subsequently adopted deferasirox as the major oral chelator. The main clinical

data of the 2 oral chelators which have guided clinical practice are summarised

below:

a. Deferiprone:

The efficacy of deferiprone as a single agent has been evaluated using serum

ferritin alone for assessment; there are trials demonstrating both the presence28

and absence29, 30 of efficacy. With respect to LIC, a recent Cochrane review

found no definitive evidence showing efficacy due to the data being

“handicapped” by pronounced differences in baseline LIC, variable presence of

Hepatitis C, and wide variation in treatment duration among studies.31 For

cardiac iron, significant benefit of deferiprone in reversing cardiac iron loading

15

has been demonstrated30 and further results from randomised studies are

awaited.

Combination therapy with deferiprone and deferoxamine has been shown to be

effective, particularly in improving cardiac iron load (as assessed by T2*

assessment) .12, 32 The two agents should be administered simultaneously on

the same day - an accepted protocol is to administer deferiprone at 75-100

mg/kg/day in 3 divided doses during the day, together with desferrioxamine

overnight for at least 3 nights per week.

b. Deferasirox:

The efficacy of deferasirox was evaluated in a large phase III study which

randomised patients to receive deferasirox or desferrioxamine, concluding that

deferasirox at a dose of 20 mg/kg/day maintained and 30 mg/kg/day reduced

body iron, and that dosing was highly dependent on the mean iron intake.23 A

subsequent phase IV prospective one-year study demonstrated a significant

reduction in serum ferritin from baseline.33 The efficacy of deferasirox in

reducing liver iron has also been shown, with at least equal efficacy compared

with desferrioxamine.23, 33, 34 With respect to cardiac iron, current available data

indicate efficacy in reducing iron load as measured by cardiac T2* (see Section

B V below).34-36 The daily schedule of administering deferasirox is considered

an advantage in improving adherence. Unlike desferrioxamine, deferasirox was

also found not to affect growth in children.37

16

Hence, the issues influencing the choice of chelation agent as continuation

therapy are summarised as follows:

1. In the majority of patients, due to the effects on adherence, an oral iron

chelator is preferred. This may be deferasirox or deferiprone, depending

on physician experience and patient preference.

2. In patients susceptible to side effects of one oral chelator, the other is

trialled, if also not tolerated then the only alternative would be

desferrioxamine.

3. Reasons for administering deferiprone include the synergy with

desferrioxamine as combination therapy in chelating excess cardiac iron.

4. Reasons for ceasing deferiprone include agranulocytosis/ neutropenia,

significant abnormalities in liver function tests and severe arthralgia or

gastrointestinal side-effects, and inadequate control of iron load (see

Section B IV below).

5. Reasons for administering deferasirox include the daily regimen which

may improve adherence, and the lower incidence of neutropenia and

agranulocytosis.

6. Reasons for ceasing deferasirox include significant rises in serum

creatinine and liver function abnormalities, severe gastrointestinal

17

disturbances and allergic reactions, and inadequate control of iron load

(see Section B IV below).

IV. Adjusting iron chelation according to efficacy and toxicity

The main determinants for modification of chelator regimen or dosage are

(1) Changes in iron load as measured by the parameters detailed in

section A

(2) Intolerance of first-line agent

(3) Patient preference

(4) Risk of cardiac compromise which is associated with a high risk of

mortality

Where iron overload is not adequately controlled, adherence should be

assessed, and if suboptimal, the cause should be identified (discussed Section

C III below). Strategies to deal with reduced tolerability or effectiveness of each

agent are discussed. Modifications required due to an increased risk or the

occurrence of cardiomyopathy are summarised.

1. Desferrioxamine

For patients on desferrioxamine, the target serum ferritin is considered to be

1000 μg/L, with a range of 1000-1500 μg/L. Patients with repeated serum

ferritin levels of 2000-2500 μg/L have significantly increased cardiomyopathy

18

and mortality,4 while ferritin levels below 500 ug/L are generally considered to

be associated with an increased incidence of side-effects though this is not

universally accepted. Doses used are 40-60 mg/kg/day 5-7 days per week. An

apparent lack of efficacy is most commonly due to non-adherence (although

under-dosing may also be present in some cases), when a change to an oral

iron chelator should be considered. Many physicians on the panel would

change to deferasirox first due to the daily scheduling and the absence of

requirement for weekly full blood count monitoring, as specified for deferiprone.

A change to deferiprone in combination with desferrioxamine may be preferred

in units with greater experience in using deferiprone, particularly in patients with

significantly increased cardiac iron loading. Reduction in desferrioxamine dose

or cessation is considered in severe skin reactions or allergy; it is rare for

ophthalmologic and auditory side effects to be the cause of dose reduction.

2. Deferiprone

The registered dose of deferiprone is 75 mg/kg/day in 3 divided doses, but up to

100 mg/kg/day is commonly used, as multiple studies have shown no additional

concerns with safety.38, 39 Deferiprone is generally prescribed in combination

with desferrioxamine, which may be ceased once chelation has been optimised.

In the presence of increasing iron load, which can be due to non-adherence,

substitution by deferasirox may be considered.

19

Agranulocytosis is an important side effect. When this occurs deferiprone

should be ceased, while the occurrence of neutropenia also necessitates

treatment interruption or cessation. It is recommended for full blood counts to

be tested weekly, although the risk of agranulocytosis is much lower after

twelve months of treatment. Other adverse events such as gastrointestinal

effects, abnormal liver function tests and arthralgia, if moderate to severe, may

lead to dose reduction or a change to deferasirox or desferrioxamine.

3. Deferasirox

The recommended starting dose of deferasirox is 20-30 mg/kg/day. The

appropriate dose to achieve a negative iron balance is highly dependent on the

mean iron intake. Where there is evidence of increasing iron load, the

deferasirox dose should be increased by 5-10 mg/kg/day to a maximum of 40

mg/kg/day. A reversible and non-progressive increase in the serum creatinine is

observed in approximately one-third of patients taking deferasirox but is not

believed to be clinically significant. It is currently recommended for deferasirox

to be stopped when serum ferritin falls below 500 μg/L as adverse events are

considered to be more common below this level. However a comparison of

patients whose serum ferritin levels were >1000 μg/L with <1000 μg/L showed

no difference in the incidence of increased serum creatinine; whether lower

levels can be achieved without increased toxicity requires further study.13

20

When chelation appears to be ineffective at the maximal deferasirox dose, most

likely due to non-adherence, or when there are severe side-effects, a change to

desferrioxamine or combination desferrioxamine/deferiprone should be

considered

V. Treatment of patients with iron-overload cardiomyopathy with abnormal

ejection fraction and cardiac T2* <10 ms

1. Established cardiomyopathy

In patients with impaired cardiac function, intravenous (IV) desferrioxamine is

the drug of choice given its efficacy in reversing iron overload and improving

cardiac function.40 This is administered through a central venous access device

over 24 hours with an infusion pump. The rationale is to achieve 24-hour

chelation, minimising toxic labile plasma iron and maximising iron chelation in

cardiac tissue. The intravenous device can be associated with thrombosis and

infection. If cardiac function improves or becomes normal, IV desferrioxamine

should not be stopped immediately or reduced as this can precipitate a relapse

or deterioration.40 A dose of 50 mg/kg/day infused seven days per week has

been found to be effective and is recommended. Although the panel considers

IV desferrioxamine the drug of choice, some members or patients who do not

favour the insertion of an IV device would, as an initial step, intensify

subcutaneous desferrioxamine (e.g. to a maximum dose of 60 mg/kg/day seven

21

days per week, which can be administered by subcutaneous infusion with a

pump over 20-24 hours each day) or change to combination deferiprone and

desferrioxamine which has been shown to be effective in decreasing cardiac

iron and improving left ventricular dysfunction in patients with impaired cardiac

function.12, 32, 41, 42Although deferasirox has been shown to improve cardiac iron

(see below),35 there are no definitive data on its effectiveness in patients with

impaired ejection fraction, and studies are being performed.

2. For patients at risk of cardiomyopathy (T2*<10 ms, or LIC > 15 mg/g dw)

In patients with a normal ejection fraction but is at high risk of cardiomyopathy

indicated by a T2* <10 ms, there are three possible options – IV

desferrioxamine,40 combination deferrioxamine/deferiprone12, 32 or

deferasirox.35, 36 As noted earlier studies have clearly shown the efficacy of IV

desferrioxamine40 and combination desferrioxamine/deferiprone in reducing

cardiac iron.12, 32 There is also evidence that patients with severe cardiac iron

load (T2* 5-10 ms) but normal ejection fraction respond well to deferasirox 30-

40 mg/kg/day,34-36 with the finding in one study that some patients with severe

liver iron load may respond less well with respect to cardiac iron clearance.36

Hence until more confirmation is obtained, it may be prudent to use deferasirox

at the higher dose of 40 mg/kg/day only when T2* has reached 10 ms or above.

22

C. Special clinical scenarios and considerations

I. Iron chelation in Thalassaemia Intermedia

Thalassaemia intermedia (TI) is defined clinically by being not as severe as

transfusion-dependent thalassaemia major, nor asymptomatic as in

thalassaemia trait.43 There is a large spectrum of severity, with more severe

patients requiring intermittent transfusions. Iron overload may result from the

cumulative transfusion burden, as well as increased iron absorption and release

from the reticulo-endothelial system due to factors such as the suppression of

hepcidin. Importantly, serum ferritin often underestimates the level of iron load

in TI.44

There is a relative paucity of data on the optimal mode of chelation and

monitoring in TI.44 Most of the previous reported experience has been small

studies in the use of desferrioxamine. For deferiprone, data are also limited; one

small study indicated efficacy with significant reductions in ferritin, hepatic iron

and NTBI.45 A one-year study of >150 patients with TI treated with deferasirox is

being conducted and results are awaited.44 It has been recommended to

commence chelation when LIC > 7mg/g dry weight and serum ferritin > 400-500

μg/L.44 The Australian panel would consider this to be appropriate advice until

more evidence is available.

23

II. Iron chelation in pregnancy and lactation

Iron chelation should be ceased as soon as pregnancy is confirmed. Neither

deferasirox nor deferiprone should be used in pregnancy. In the first half of

pregnancy, desferrioxamine should not be used due to concerns with foetal

development, but in Australian practice it is generally recommenced between 16

to 20 weeks’ pregnancy to prevent exacerbation of iron overload, especially

since rapid iron loading during pregnancy has been reported.46 Others have

recommended iron chelation at the end of the second trimester only for patients

with high levels of liver or cardiac iron load.47 As cardiac dysfunction is the most

important cause of maternal mortality, it is extremely important that patients are

well chelated prior to conception.

There are few data on the use of desferrioxamine in lactation. The molecular

weight is small enough for excretion into breast milk but the effects, if any, in a

nursing infant are unknown. In many practices, unless the mother has severe

iron overload at risk of cardiomyopathy, breast feeding is encouraged for 6

weeks after delivery without iron chelation. There are no data on deferasirox or

deferiprone in lactation and neither is recommended.

III. Compliance/ Adherence

Clinical studies have shown the most important cause of suboptimal chelation to

be non-adherence.2 The causes are varied, and need to be approached

individually, ranging from difficulty of administering subcutaneous injections,

24

other psychological issues to dosing frequency.3 Strategies used to improve

compliance range from a change to oral medication, aide-memoires and

psychological counselling. Interventions for non-adherence are challenging and

are examined by Cochrane reviews in which many specialised publications are

included.48

Conclusions

Iron chelation is a crucial concern in the management of patients with

transfusion-dependent congenital anaemias, especially thalassaemia major.

Failure to achieve iron control results in morbidity and mortality. While a

patient’s adherence to iron chelation regimens remains one of the most

important factors in prognosis, the advent of new oral agents for iron chelation

has provided additional options. New methods of iron monitoring such as MRI

have also provided the means to monitor iron load more accurately, although

access to these investigations is still limited. This should be improved in the

future so as to increase the efficacy and safety of iron chelation. 

Acknowledgements

Novartis Australia provided support and facilitated the members of the panel to

convene in a workshop, but the opinions expressed in this document are the

responsibility of the authors. We thank Dr. Juliana Teo for advice on her

paediatric protocols.

25

Authors contributions:

PJH and DKB chaired the workshops and subsequent discussion at which the

guidelines were formulated. PJH wrote and revised the manuscript; DKB, LT,

RL and LC reviewed the manuscript and contributed to revisions.

26

Table I. Measurements of hepatic iron and clinical implications in transfusion-dependent patients with beta-thalassaemia (Adapted from Olivieri & Brittenham, 1997)

Hepatic iron (mg/g dry weight)

Severity Implications*

<1.2 Normal Nil

3 -7 Mild “Optimal” level

7 -15 Moderate Increased risk of complications

>15

Severe Increased risk of cardiac disease and early death**

*As noted in Section A V, discrepancies can occur in individual patients between liver and cardiac iron load, most likely due to differential iron loading and clearance in the heart and liver. Thus while the thresholds in this table are useful in indicating the risk of hepatic complications and an overall risk, some patients with “optimal” levels of liver iron according to the table may still experience high cardiac iron loading. The latter is more accurately assessed by specific measurement of cardiac iron (see section A IV on cardiac MRI and Table II).

** The measurement of T2* by cardiac MRI provides a more accurate assessment of cardiac risk (see Section A IV and Table II). However the category of greater than 15 mg/g/dw liver iron would still constitute “severe” risk with respect to the sequelae of liver iron load and overall risk assessment, including the risk for cardiac iron loading.

27

Table II. Assessment of iron load and cardiac risk by cardiac MRI 16

Cardiac T2* (ms) Cardiac iron load and risk

> 20 Normal

10 – 20 Moderate to severe

< 10 Severe

28

Table III. Summary of available iron chelators, characteristics of administration, excretion and side-effects.

Desferrioxamine Deferiprone Deferasirox

Usual dose 20 – 60 mg/kg/day 75 – 100 mg/kg/day 20 – 40 mg/kg/day

Route

s.c., i.v.

s.c. over 8 – 12 hrs 5 – 7 nights per week

p.o.

3 times a day

p.o.

once a day

Half-life 20-30 min 3 – 4 h 8 – 16 h

Excretion Urinary, faecal Urinary, some faecal

Faecal

Main side-effects

• Injection site – lumps, infections

• Bone changes • Ototoxicity • Ophthalmic

changes • Increased risk of

yersinia & klebsiella infections

• Arthralgia/ arthritis

• Abnormal liver function tests

• Neutropenia, agranulocytosis

• Rash • Diarrhoea,

nausea • Abnormal renal

function (reversible, non-progressive)

• Abnormal liver function tests

29

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